Not yet recruitingRare disease

Tambiciclib Added to Venetoclax and Azacitidine for Newly Diagnosed Acute Myeloid Leukemia in Patients Who Did Not Respond After Two Treatment Cycles

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What is this trial about?

A plain-language summary of the goals, design and what participants do

This study is being done in acute myeloid leukemia, a fast-growing cancer of the blood and bone marrow. The treatment being studied is tambiciclib given by vein, added to the standard treatment with venetoclax taken by mouth and azacitidine given by injection under the skin. The purpose of the study is to see whether adding tambiciclib can help people who did not improve enough after the first two treatment cycles with venetoclax and azacitidine alone.

The study is a Phase II trial, which means it is an earlier study that looks at how well the treatment works and how safe it is. It is open-label, so everyone knows which treatment is being given, and randomized, which means treatment is assigned by chance. The course of the study involves treatment with the study drugs over several cycles, with regular medical follow-up to watch for response and side effects. The study also checks for common and serious side effects and how long people remain free from worsening of the disease.

The research process

The trial runs in 5 steps – from screening to follow-up. Each step says what happens and what the team monitors.

Step 1
Study treatment starts
You start the trial after joining the study and begin treatment with venetoclax taken by mouth at a dose of 400 mg.
You also receive azacitidine by subcutaneous injection at a dose of 75 mg per square meter of body surface area.
The study uses tambiciclib as the test treatment, given by intravenous infusion at a dose of 30 mg.
The trial compares treatment with tambiciclib added to the standard treatment of venetoclax and azacitidine.
The study is open-label, which means that the treatment given is known and not hidden.
Step 2
First two treatment cycles
You continue treatment through the first two cycles of venetoclax and azacitidine.
The trial checks whether you achieve at least mlfs after these two cycles.
mlfs means morphologic leukemia-free state, which is a state in which no clear signs of leukemia are seen in the bone marrow under the microscope.
If you have not achieved at least mlfs after the first two cycles, the study continues with the addition of tambiciclib.
Step 3
Treatment with tambiciclib added
You receive tambiciclib as an add-on treatment together with venetoclax and azacitidine.
The dose of tambiciclib is 30 mg given by intravenous infusion.
The study uses two listed forms of tambiciclib: 100 mg/10 mL solution for injection and 100 mg/20 mL solution for injection.
The trial evaluates whether adding tambiciclib improves the chance of response by the end of course 2.
Step 4
Response assessment after course 2
After course 2, the study measures the main result called overall response rate, or orr.
orr includes complete response, complete hematological response, complete response with incomplete blood count recovery, and mlfs.
complete response means no clear signs of disease are found.
complete hematological response means blood counts have improved to the required level.
complete response with incomplete blood count recovery means the disease is controlled, but blood counts have not fully returned to normal.
Step 5
Safety and follow-up during treatment
During the trial, the study records adverse events, which are unwanted medical problems or side effects.
The study also records severe adverse events, which are more serious side effects.
These events are graded using nci-ctcae 5.0, which is a standard system for rating how serious side effects are.
The study follows event-free survival, which is the time from the first treatment day to treatment failure, relapse, or death from any cause.
Treatment failure means not reaching at least mlfs after the second treatment cycle.
The study also follows overall survival, which is the time from the first treatment day to death from any cause.

Who can join the trial?

19 criteria

Be an adult, meaning 18 years of age or older.
Be willing and able to give informed consent, which means agreeing to join the study after understanding what it involves.
Have a confirmed diagnosis of acute myeloid leukemia based on tissue or cell testing.
Have at least 20% blasts in the bone marrow and/or blood at the time of diagnosis, unless the leukemia has a specific genetic change that meets the study rules.
Have already received exactly 2 treatment cycles of standard venetoclax + azacitidine before joining the study.
Have had an insufficient response to the first 2 cycles of venetoclax + azacitidine, meaning the disease has not reached at least morphological leukemia-free state after cycle 2. This means leukemia cells are still seen under the microscope.
Have measurable disease at enrollment, meaning at least 5% blasts in the bone marrow.
Not have disease that is only outside the bone marrow, called extramedullary-only disease.
Have an ECOG performance status of less than 2, meaning the person is able to do most daily activities and is not severely limited by illness.
Have normal organ function, including:
- Bilirubin no more than 1.5 times the upper normal limit, except some people with Gilbert’s syndrome may be allowed if their bilirubin is lower than 3 times the upper normal limit or their direct bilirubin is less than 1.5 times the upper normal limit.
- AST and ALT liver tests no more than 2.5 times the upper normal limit, or no more than 5 times the upper normal limit if the liver is known or suspected to have leukemia cells.
- Kidney function with creatinine clearance, or a similar kidney test, of at least 50 mL/min.
- Have a white blood cell count below 25,000/µL. If needed, the count may be lowered with hydroxyurea, a medicine used to reduce blood cell counts. Using a blood-filtering procedure called leukapheresis only to make the person eligible is not allowed.
- Have recovered to grade 1 or lower from side effects caused by the first 2 cycles of venetoclax + azacitidine. Grade 1 means mild side effects. This does not include hair loss, tiredness, hormone-related problems, lab changes controlled with treatment, or blood-related side effects.
- If the patient is a woman who can become pregnant, she must agree to use a highly effective birth control method during treatment and for 6 months after the last study dose.
- If a woman who can become pregnant uses a hormonal birth control method, she must also use a barrier method, such as a condom, because the study drug may affect hormonal contraception.
- If the patient is a woman who can become pregnant, she must have a negative pregnancy test in the blood before the first study dose.
- If the patient is a man whose partner is pregnant or can become pregnant, he must use a condom during treatment and for 3 months after the last study dose.
- Women who can become pregnant and men whose partner is pregnant or can become pregnant must agree to not donate sperm or eggs during treatment and through the full follow-up period for birth control.

Who cannot join the trial?

18 criteria

Having received systemic treatment for acute myeloid leukemia (AML) within the last 30 days, except for ATRA if it was used because AML was thought to be a different leukemia type, or hydroxyurea or cytarabine if they were used urgently to lower the number of leukemia cells or keep the disease stable, with a total cytarabine dose of no more than 1 gram, and except for the planned VEN+Aza treatment.
Having HIV infection, unless all of the following are true: the CD4+ count is at least 350 cells/uL (a measure of immune cells), there were no AIDS-defining opportunistic infections in the last 12 months (serious infections that happen when the immune system is weak), the patient has been on stable antiretroviral therapy (ART) for at least 4 weeks, and the HIV viral load is below 400 copies/mL before joining the study.
Having any other uncontrolled illness or condition that, in the investigator’s judgment, could put the patient at risk.
Taking medicines that are strong CYP3A4 inhibitors or strong inducers within 7 days before the first dose. CYP3A4 is a liver enzyme that helps break down medicines. Also excluded is recent use of foods or herbal products that can affect this enzyme, such as Seville orange, grapefruit, pomelos, star citrus fruits, or St. John’s wort. Some antifungal medicines may be allowed only if the study doctor decides they are necessary.
Taking medicines known to prolong the QT interval that cannot be stopped before study entry, except for azole antifungal medicines. The QT interval is a measurement on the heart tracing that shows how the heart resets between beats.
Having had a severe stroke or bleeding inside the skull within the last 6 months.
Having had major surgery within the last 4 weeks.
Having a known allergy or hypersensitivity to the study drug, any ingredient in it, or any medicine given with the study. Hypersensitivity means an unusual or strong allergic reaction.
Being pregnant or breast-feeding.
Having used any other CDK9 inhibitor before. A CDK9 inhibitor is a medicine that blocks a specific protein used by cells.
Having had wide-field radiotherapy within 28 days or limited-field radiotherapy for symptom relief within 7 days before the first dose. Radiotherapy means treatment with radiation.
Having symptomatic central nervous system (CNS) involvement. CNS means the brain and spinal cord. Patients with no symptoms may still join only if the CNS disease has been stable for at least 4 weeks after CNS-directed treatment and steroid medicine is stable or decreasing.
Receiving any investigational medicine in another clinical trial within 30 days before screening. Investigational medicine means a drug still being tested.
Taking corticosteroids at a dose higher than 25 mg of prednisone per day or the equivalent. Corticosteroids are anti-inflammatory medicines. Inhaled and skin creams are allowed.
Having uncontrolled high blood pressure, especially if there is a history of repeated hypertensive crisis or hypertensive encephalopathy. A hypertensive crisis is a very dangerous blood pressure spike, and hypertensive encephalopathy is brain trouble caused by very high blood pressure.
Having severe heart or blood vessel disease within the last 6 months, including: heart failure that needs treatment and is severe, serious abnormal heart rhythm, a recent heart attack or unstable chest pain, or a QTcF of 480 msec or higher on the screening heart test. QTcF is a corrected heart timing measurement. Patients with certain pacemakers may be treated differently, but people with a history of fainting or important rhythm problems while using the pacemaker are excluded. Patients with a history of serious blood clots in veins or arteries may also be excluded if the investigator thinks the risk is too high.
Having another cancer within the last 2 years, except for certain early or well-treated cancers such as treated cervical cancer in situ, localized skin squamous cell cancer, basal cell cancer, prostate cancer not needing treatment, ductal carcinoma in situ of the breast, and superficial non-muscle invasive bladder cancer except T1 lesions and carcinoma in situ.
Having active hepatitis B or active hepatitis C infection. Hepatitis B and C are viral infections that affect the liver. People with chronic hepatitis B who need treatment must already be on treatment that keeps the virus suppressed before joining. People with hepatitis C may join only if the infection is stable and there is no risk of serious liver failure.

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Verified sites

All sites with verified contact details – recruitment status may not be available; ask directly

Azienda Ospedaliera Universitaria Federico II Di Napoli
Verified
Naples, Italy
Azienda Unita Sanitaria Locale Della Romagna
Verified
Faenza, Italy
Istituto Oncologico Veneto
Responsive
Padua, Italy

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Investigated drugs

Tambiciclib
is the study drug being added to the usual treatment. It is given by intravenous infusion, meaning it goes directly into a vein through a drip. In this trial, it is being tested to see if it can help patients with newly diagnosed acute myeloid leukemia who did not get enough benefit from the first two cycles of standard treatment.
Azacitidine
is one of the standard medicines used in the trial. It is given as an injection under the skin. It is used to treat the leukemia as part of the usual treatment plan, and it is given together with venetoclax.
Venetoclax
is another standard medicine used in the trial. It is taken by mouth. It is used with azacitidine to treat the leukemia, and the study is looking at what happens when tambiciclib is added to this usual combination.

What is already known about the treatment

Tambiciclib
Tambiciclib is given as a solution for injection by intravenous infusion, which means it is delivered slowly into a vein by a healthcare professional. It is an investigational medicine, so its full place in medical practice is still being studied and it is not yet an established standard treatment in the medical literature. In this trial, it is being tested for acute myeloid leukemia, and it is thought to work by blocking cyclin-dependent kinases, proteins that help cancer cells grow and divide. This puts it in the class of targeted anti-cancer medicines, especially cell cycle inhibitors.
Azacitidine
Azacitidine is usually given as a subcutaneous injection, which means it is injected under the skin by a healthcare professional. It is an approved and well-known medicine in cancer care, especially for blood cancers, and it is widely described in medical literature. It is used mainly for acute myeloid leukemia and myelodysplastic syndromes, and it works by interfering with how cancer cells copy and use their genetic material, which can slow their growth and may help abnormal cells mature more normally. It is classified as an anti-cancer medicine and a DNA methylation inhibitor, also known as a hypomethylating agent.
Venetoclax
Venetoclax is taken by mouth as a tablet, usually once daily according to the treatment plan set by the doctor. It is an approved medicine and is well established in medical practice and medical literature, especially for certain blood cancers. It is used for acute myeloid leukemia and some types of leukemia and lymphoma, and it works by blocking a protein called BCL-2 that helps cancer cells avoid natural cell death. This medicine is classified as a targeted anti-cancer drug and a BCL-2 inhibitor.

Investigated diseases

Acute myeloid leukemia - A cancer of the blood and bone marrow in which immature myeloid cells grow too quickly and do not mature normally. These abnormal cells crowd out healthy blood cells, and the disease can develop and worsen rapidly if the abnormal cells continue to build up.